The aim of this project is to develop a thorough understanding at the genetic and molecular level of holy Drosophila cells translate a two-fold difference in the relative number of X chromosomes (the X/A ratio) into the vast number of qualitative and quantitative differences in gene expression that eventually distinguish males from females. This understanding will provide the basis for meaningful comparisons among different species with respect to their sex determination strategies, and within Drosophila for gene networks that direct different categories of developmental processes. Comparisons such as these should lead to profound insights into how the development of higher organisms is genetically programmed and how that programming evolves. Only with such in depth understanding will it be possible to deal effectively with human genetic diseases. Previous analysis of the target of the Drosophila sex determination signal, the gene Sex-lethal, led to a breakthrough in the analysis of the XIA signal itself with the discovery of the sisterless genes. The sis genes comprise the numerator of this parameter. Only rudimentary information is yet available on sis gene function, but from what little has been learned it is evident that the control of sexual development overlaps in a very significant way with the control of nervous system development. The genes involved in the overlap are relatives of the myc oncogene. By providing a convenient handle for the analysis of myc-family proteins, sex determination may supply clues that are important for understanding some aspects of human cancer. The two sis genes already known will be exhaustively characterized in order to understand specifically how they operate in sex determination and how that function is related to their other functions. The discovery of the sis genes will be exploited thoroughly in order to identify and characterize other genes with related actions, including "denominator" elements of the XIA ratio. The goal is to understand what the XIA signal elements have in common that might account for their involvement in sex determination. Another aspect of the study will draw on the vast amount of information available on the signal target, Sxl, in an attempt to understand specifically how, and thereby why, Drosophila sex determination in the germ line is so different from that in the soma. An incentive for bringing the level of understanding of germline sex determination nearer to that for the soma is the fact that germline sex determination seems to have much more in common than somatic with human sex determination. The third focus of the present study is on the primary sex determination gene itself, Sxl, asking the question of how this complex gene's multiple developmental functions are encoded in its DNA. Sxl information will be deciphered through developmental characterization of Sxl products, and by correlations that emerge between the nature of DNA changes and their functional consequences in an extensive analysis of point mutant alleles and small deletions.